GB virus C (GBV-C) is a common human infection that, until recently, was not thought to be associated with any disease. Due to the perceived lack of pathogenicity, blood products are not screened for GBV-C, even though ~2% of U.S. blood donors are viremic at the time of donation. A recent large, Canadian, population-based case- control study found an association between GBV-C and non-Hodgkin lymphoma (NHL; odds ratio of 2.72 [95% CI 1.22-6.69]). Unfortunately, due to an imbalance in sample availability, the cases were not well matched with the controls. Nevertheless, previous studies, and several lines of evidence support biological plausibility for a relationship between GBV-C and NHL, the 6th most common cancer in the US. Specifically, GBV-C infection causes persistent infection of humans, replicates in B and T lymphocytes, prolongs survival of lymphocytes and is associated with delayed apoptosis in vivo and in vitro. Specifically, two viral proteins (nonstructural protein 5A and envelope glycoprotein E2) inhibit Fas-mediated apoptosis in lymphocyte cell lines. In addition, hepatitis C virus is an accepted risk for NHL, and GBV-C is closely related to HCV, sharing considerable amino acid homology (up to 80%) in several conserved nonstructural, replication-related proteins. In Specific Aim 1, we will determine whether GBV-C viremia is associated with the risk of developing NHL by using an existing clinic-based case-control study of 2500 cases and 2500 controls from the upper Midwestern US. In Aim 2 we will assess the relationship of past GBV-C infection (antibody positivity) on risk of NHL and prognosis, and in Aim 3 we will determine if GBV-C is associated with event-free and overall survival in NHL. As a secondary analysis, the association of GBV-C with NHL subtypes (diffuse large B cell lymphoma, other B-cell lymphomas, follicular lymphoma, or T cell lymphomas) will be examined, although power to assess subtype-specific associations was limited. This study fills a critical need to determine in an independent, rigorously-designed, and well-powered case-control study from North America whether GBV-C virus is associated with NHL risk and prognosis. Screening blood donors for GBV-C would be costly and require deferral of approximately 2% of donors. However, if GBV-C is associated with NHL, reconsideration of current blood donor screening testing would be necessary to protect the blood supply. By using an established case-control study cohort, for which the samples will be available at the start of this grant, and by working with leaders in GBV-C and lymphoma epidemiology and clinical research, the study has a high probability of success. The laboratory that will perform the GBV-C diagnostic testing developed the state-of-the-art approaches to be utilized, and has extensive published experience related to GBV-C research. The evaluation of a role for this virus in NHL prognosis is novel and innovative. Regardless of the results obtained, this study has the potential to have a great impact on public health regarding transfusion medicine, and potentially in the clinical management of NHL patients.